Human recombinant activated protein C-coated stent for the prevention of restenosis in porcine coronary arteries

Abstract

Activated protein C (APC), an endogenous protein, inhibits inflammation and thrombosis and interrupts the coagulation cascade. Here, we investigated the effect of human recombinant APC on the development of neointimal hyperplasia in porcine coronary arteries. Yukon Choice bare metal stents were coated with 2.6 µg APC/mm2. Under general anesthesia, APC-coated and bare stents were implanted in the left anterior descending and circumflex coronary arteries of 10 domestic pigs. During the 4-week follow-up, animals were treated with dual antiplatelet therapy and neointimal hyperplasia was evaluated via histology. Scanning electron microscopy indicated successful but unequal coating of stents with APC; nearly complete drug release occurred within 4 h. Enzyme-linked immunosorbent assay revealed that intracoronary stent implantation rapidly increased the levels of monocyte chemoattractant protein-1, an effect that was inhibited by APC release from the coated stent. Fibrin deposition and adventitial inflammation were significantly decreased 1 month after implanting APC-coated stents versus bare stents, paralleled by significantly smaller neointimal area (0.98 ± 0.92 vs. 1.44 ± 0.91 mm2, P = 0.028), higher lumen area (3.47 ± 0.94 vs. 3.06 ± 0.91 mm2, P = 0.046), and lower stenosis area (22.2 ± 21.2 % vs. 32.1 ± 20.1 %, P = 0.034). Endothelialization was complete with APC-coated but not bare (90 %) stents. P-selectin immunostaining revealed significantly fewer activated endothelial cells in the neointima in the APC group (4.6 ± 1.9 vs. 11.6 ± 4.1 %, P < 0.001). Thus, short exposure of coronary arteries to APC reduced inflammatory responses, neointimal proliferation, and in-stent restenosis, offering a promising therapy to improve clinical outcomes of coronary stenting. However, coating stents with APC for prolonged, controlled drug release remains technically challenging.

Bioactive Anti‐Thrombotic Modification of Decellularized Matrix for Vascular Applications

“…Adsorption was chosen as the surface modifi cation strategy because prior work demonstrated that carbodiimide-mediated crosslinking of SIS reduced the hemocompatibility. [ 24 ] Furthermore, permanent attachment of heparin and TM was not considered necessary because even short-term administration of either thrombomodulin [ 37 ] or APC [ 38 ] has shown a signifi cant reduction in long-term intimal hyperplasia, and multiple inhibitory blood plasma proteins would eventually degrade the activity of both modifi cations. [ 21 ] Baboon Carotid Endothelial Cell Culture : ECs were isolated from baboon carotid arteries as previously described.…”

Control of Blood Coagulation by Hemocompatible Material Surfaces—A Review

“…Anticoagulant proteins & contact system specific inhibitors. Anticoagulant proteins, including thrombomodulin [ 190 , 191 , 192 , 193 ], activated protein C [ 194 ], or TFPI [ 195 ], have been immobilized to biomaterial surfaces of vascular stents or vascular grafts. For example, thrombomodulin has been covalently immobilized to nitinol surfaces which were pre-treated with amino-terminated organosilanes to generate an aminated surface for further reaction [ 196 ].…”

A Recombinant Fusion Construct between Human Serum Albumin and NTPDase CD39 Allows Anti-Inflammatory and Anti-Thrombotic Coating of Medical Devices

“…With the passivation strategy, physical and chemical modifications are made to the materials and surfaces to reduce their inherent thrombogenicity. Bioactive surface coatings are achieved by permanent immobilization via an active agent or drug to directly inhibit the coagulation cascade and prevent neointimal hyperplasia [ 11 , 12 , 13 ]. In addition to these, administration of anti-platelet or anti-coagulation therapeutics is used as a treatment to prevent device-induced thrombosis [ 13 , 14 , 15 , 16 ].…”